A Mild and Convenient Semi-Synthesis of Docetaxel from 10-Deacetyl Baccatin III

Article abstract of DOI:10.2174/157017810791824892

A novel protocol for the semi-synthesis of docetaxel was achieved in four steps from 10-deacetyl baccatin III with an overall yield of 50%. The key step is the selective protection of the C(7) and C(10) hydroxyl groups of 10-deacetyl baccatin III, utilizi

Full text of DOI:10.2174/157017810791824892

450
Letters in Organic Chemistry, 2010, 7, 450-452
A Mild and Convenient Semi-Synthesis of Docetaxel from 10-Deacetyl
Baccatin III
Hui Zhou, Dahai Chen, Hongwei Gao and Qingeng Li*
College of Pharmacy, Chongqing Medical University, 400016, P.R., China
Received September 21, 2009: Revised February 02, 2010: Accepted February 17, 2010
Abstract: A novel protocol for the semi-synthesis of docetaxel was achieved in four steps from 10-deacetyl baccatin III
with an overall yield of 50%. The key step is the selective protection of the C(7) and C(10) hydroxyl groups of 10-
deacetyl baccatin III, utilizing benzyl chloromate as a selective protecting reagent, which are capable of being
conveniently removed by Pd/C under hydrogen atmosphere.
Keywords: Docetaxel, semi-synthesis, 10-DAB III, benzyl chloromate.
INTRODUCTION
introduced and removed under mild conditions, especially in
the extremely sensitive taxane skeleton.
Docetaxel is a semi-synthetic, second-generation taxane.
It displays potent and broad antineoplastic properties [1,2].
Docetaxel is considered
antimicrotuble agent than doxorubicin, paclitaxel, and
fluorouracil [1]. In view of the significance of docetaxel in
cancer therapy, a demand of large quantity of docetaxel is
expected. At the same time, the total synthesis of docetaxel
is not commercially practical due to the lengthy synthetic
steps as well as the high cost involved. Thus, highly efficient
and practical semi-synthesis is a favorable solution. Semi-
Currently, triethylsilyl(TES) [4], trichloroethoxycarbonyl
(Troc) [5], tribromoacetyl [6] have been reported as the
protecting groups for the C(7) and C(10) hydroxyl groups of
10-DAB III. However, always a series of by-products were
obtained when using TES and Troc as the protecting group.
This led to the difficulty of purification. Sisti’s group [7] has
developed a method utilizing the benzyloxycarbonyl (Cbz)
group to protect the C(7) and C(10) hydroxyl groups, but it
requires the low temperature of -78 oC and 1.5 equivalent of
a more effective cytotoxic
OH
7
OH
7
HO
10
O
HO
10
O
O
O
NH
O
13
1
13
1
O
O
O
HO
O
O
OH
OH
OH
O
O
O
O
O
O
Docetaxel, 1
10-DAB III, 2
synthesis of docetaxel generally utilizes a key coupling
reaction of a suitably protected baccatin III derivative with a
chiral C(13) side chain [6]. 10-Deacetyl baccatin III(10-DAB
III) [3], which possesses the skeleton of taxol and is
commercially extracted from the needle of Taxus baccata L.,
the European yew, is the most readily available and abundant
taxane. Its conversion to docetaxel first requires selective
protection of the C(7) and C(10) hydroxyl groups. And the
selective protecting groups are required to be easily
n-butyl lithium, which is very sensitive to moisture. Herein,
we wish to report benzyl chloromate as a practical selective
protecting reagent for 10-DAB III under a mild condition
and its application in the semi-synthesis of docetaxel.
RESULTS AND DISCUSSIONS
In the preliminary study, we investigated the selective
protection of 10-DAB III utilizing benzyl chloromate in the
presence of 4-(dimethylamino)pyridine (DMAP). Fortuna-
tely, the desired C(7), C(10) carbonate was obtained in high
yield and purity (Table 1, entry 1). In addition, p-NO2-benzyl
chloromate was investigated as the protecting reagent.
*Address correspondence to this author at the College of Pharmacy,
Chongqing Medical University, P. R., 400016, China; Tel: 86-23-68485378;
Fax: 86-23-68485161; E-mail: liqingeng@cqmu.edu.cn
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© 2010 Bentham Science Publishers Ltd.

A Mild and Convenient Semi-Synthesis of Docetaxel
Letters in Organic Chemistry, 2010, Vol. 7, No. 6
451
Table 1. The Selective Protection of 10-DAB IIIa
O
OR2
R3O
O
OH
HO
O
O
Cl
R1
3a: R = H
O
R4O
O
OH
OAc
HO
O
3b: R = p-NO2
OBz
OH
O
O
4a: R2 = benzyloxycarbonyl, R3 = H, R4 = H
4b: R2 = p-N02-benzyloxycarbonyl, R3 = H, R4 = H
5a: R2 = H, R3 = benzyloxycarbonyl, R4 = H
5b: R2 = H, R3 = p-N02-benzyloxycarbonyl, R4 = H
6a: R2 = benzyloxycarbonyl, R3 = benzyloxycarbonyl,
R4 = H
DMAP/THF/40-60 oC
O
2
6b: R2 = p-N02-benzyloxycarbonyl, R3 = p-N02-
benzyloxycarbonyl, R4 = H
7a: R2 = benzyloxycarbonyl, R3 =benzyloxycarbonyl,
R4 =benzyloxycarbonyl
7b: R2 = p-N02-benzyloxycarbonyl, R3 = p-N02-
benzyloxycarbonyl, R4 = p-N02-benzyloxycarbonyl
Ratio (%)b
Entry
Protecting Reagent
4
5
6
7
1
2
3a
3b
2.4(4a)
1.0(4b)
0.3(5a)
0.2(5b)
97.3(6a)
98.8(6b)
N.D.c(7a)
N.D.(7b)
aReaction was conducted with 2(28 mmol) in THF(150 mL) with DMAP(28 mmol) and 3(0.37 mol/L in THF, 150 mL) at 40-60 oC.
bDetermined by HPLC.
cN. D. = Not Detected.
Similar results were obtained (Table 1, entry 2) and therefore
we selected benzyl chloromate to continue on with.
docetaxel. The reaction conditions and their results were
summarized in Scheme 1. Coupling of 7,10-diprotected
baccatin III(6a) with commercially available side-chain 10
was carried out by using NaN(TMS)2 and NaH to afford 8 in
80% yield via column chromatography. Upon treatment of 8
with Pd/C under a hydrogen atmosphere, gave pure 9 in 98%
yield after filtration and concentration. Finally, the removal
of 2’-acetal with AcOH/H2O afforded the desired docetaxel
in 78% yield.
Subsequently, several organic bases have been examined.
The results are summarized in Table 2. When aliphatic
tertary amine, triethyl amine, was used instead of DMAP,
many by-products were found without any desired products
(Table 2, entry 1). When pyridine was used, only mono-
protection of C(7) or C(10) hydroxyl of 10-DAB III were
found(Table 2, entry 2). When inorganic bases such as
Na2CO3 or NaOH were mixed with 10-DAB III, many by-
products were formed, therefore DMAP was the base of
choice. And the desired C(7), C(10) carbonate was obtained
with the isolated yield of 81%.
In conclusion, we have developed a new method for
docetaxel with an overall yield of 50% from 10-DAB III.
The key step is the highly selective protection of the C(7)
and C(10) hydroxyl groups of 10-DAB III, utilizing benzyl
chloromate as a selective protecting reagent and DMAP as
coupling reagents in a mild condition. The method will
In light of our success in developing selective protection
of 10-DAB III, we decided to apply it into the synthesis of
Table 2. The Selective Protection of 10-DAB III with Different Basesa
3/base/THF/40-60 oC
2
4a + 5a + 6a + 7a
Ratio(%)b
Entry
Base
4a
5a
6a
7a
1
2
3
Et3N
N.D.c
3.02
2.35
N.D.
1.03
0.31
N.D.
N.D.
N.D.
N.D.
N.D.
Pyridine
DMAP
97.20d
aReaction was conducted with 2(28mmol) in THF(150 mL) with a certain base(28 mmol) and 3(0.37 mol/L in THF, 150 mL) at 40-60 oC.
bDetermined by HPLC.
cN. D. = Not Detected.
dThe isolated yield is 81%.

452 Letters in Organic Chemistry, 2010, Vol. 7, No. 6
Zhou et al.
OCOOBn
BnOOCO
O
OCOOBn
BnOOCO
O
Boc
Ph
NH
O
a
O
O
O
HO
OH
OAc
O
OH
OAc
OBz
OBz
O
Ph
O
Boc
N
8
6a
OH
HO
O
O
Boc
10
O
NH
O
c
b
O
1
Ph
O
OH
OAc
O
OBz
O
9
Scheme 1. Semi-synthesis of Docetaxel.
Reagents and conditions: (a) 10, NaH, NaN(TMS)2, -40 oC, THF, 2.5h, 80%; (b) Pd/C, H2, THF, r.t., 5h, 98%; (c) AcOH/H2O(4:1, v/v), r.t.,
4h, 78%.
benefit from the easy handle, high yield and the high
purity[8] of docetaxel.
REFERENCES
[1]
[2]
[3]
Lyseng-Williamson, K. A.; Fenton, C. Docetaxel: a review of its
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from Taxus baccala L. and in vitro inhibition of depolymerization
of microtubules into tubulin. C. R. Acad. Sci. Paris, II, 1981, 293,
501.
EXPERIMENTAL SECTION
C-7, C-10-dibenzyloxycarbonyl-10-Deacetyl baccatin III
(6a)
10-DAB III (15g, 28mmol) and DMAP (3.4g, 28mmol)
were dissolved in anhydrous THF (150 mL) and the solution
was warmed to 40 C. Benzyl chloromate (0.37 mol/L in
[4]
[5]
[6]
Appendino, G.; Belloro, E.; Jakupovic, S.; Danieli, B,; Jakupovic,
J.; Bombardelli, E. Synthesis of paclitaxel (docetaxel)
/ 2-
o
deacetoxytaxinine J dimers. Tetrahedron, 1999, 55, 6567.
Guéritte-Voegelein, F.; Sénilh, V.; David, D.; Guénard, P. P.
Chemical studies of 10-deacetyl baccatin III : Hemisynthesis of
taxol derivatives. Tetrahedron, 1986, 42, 4451.
Heo, J. H.; Park, S. J.; Kang, J. H.; Lee, I. S.; Lee, J. S.; Park, Y. J.;
Kim, K. S.; Lee, J. Y. Development of New Efficient Synthetic
Methods for Docetaxel. Bull. Korean. Chem. Soc., 2009, 30, 25,
and the references therein.
Sisti, N. J.; Swindell, C. S.; Chander, M. C. Intermediate for use in
docetaxel synthesis and production method therefor. U.S. Patent, 6,
107, 497, 2000.
The purity of docetaxel synthesized by our method was 99.6%
which was determined by HPLC. (YMC C18(150ꢁ46mm,5μm),
Methanol/Acetonitrile/H2O = 33/25/42, flow rate 1.5 mL/min,
detection at 232 nm, tR 14.8 min).
THF, 150 mL) was added dropwise over 1h, and the solution
o
was warmed to 60 C, and stirred for an additional 30 min.
The mixture was then cooled to r.t., filtrated, and washed
with THF. The combined filtrate was concentrated under
reduced pressure, and the crude product was purified by
column chromatography to obtain pure 6a as a white solid
(18g, 81%). 13C NMR (125 MHz, CDCl3) ꢀ 10.6, 15.4, 20.1,
22.6, 25.6, 26.6, 33.4, 38.4, 42.7, 47.4, 56.3, 68.0, 68.0, 69.9,
70.1, 74.3, 75.6, 76.4, 78.7, 79.0, 80.6, 83.9, 128.3, 128.3,
128.4, 128.44, 128.5, 128.6, 128.7, 129.3, 130.1, 131.5,
133.7, 135.2, 135.3, 145.6, 154.2, 154.2, 167.0, 170.7, 202.0;
ESI-MS calcd. for C45H48O14Na [M+Na]+: 835.3, found
835.6.
[7]
[8]
ACKNOWLEDGEMENT
We appreciate the financial support from the National
Natural Science Foundation of China (No. 20902114).